Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1gene.[5][6] Protein S plays a role in coagulation.
History
Protein S is named for Seattle, Washington, where it was originally discovered and purified[7] by Earl Davie's group in 1977.[8]
Additionally, protein S has a peptide between the Gla domain and the EGF-like domain, that is cleaved by thrombin. The Gla and EGF-like domains stay connected after the cleavage by a disulfide bond. However, protein S loses its function as an APC cofactor following either this cleavage or binding C4BP.[11]
Function
The best characterized function of Protein S is its role in the anti coagulation pathway, where it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Only the free form has cofactor activity.[12]
Protein S binds to negatively charged phospholipids via the carboxylated Gla domain. This property allows Protein S to facilitate the removal of cells that are undergoing apoptosis, a form of structured cell death used by the body to remove unwanted or damaged cells. In healthy cells, an ATP (adenosine triphosphate)-dependent enzyme removes negatively charged phospholipids such as phosphatidyl serine from the outer leaflet of the cell membrane. An apoptotic cell (that is, one undergoing apoptosis) no longer actively manages the distribution of phospholipids in its outer membrane and hence begins to display negatively charged phospholipids on its exterior surface. These negatively charged phospholipids are recognized by phagocytes such as macrophages. Protein S binds to the negatively charged phospholipids and functions as a bridge between the apoptotic cell and the phagocyte. This bridging expedites phagocytosis and allows the cell to be removed without giving rise to inflammation or other signs of tissue damage.
Protein S does not bind to the nascent complement complex C5,6,7 to prevents it from inserting into a membrane. This is a different complement protein S AKA vitronectin made by the VTN gene, not to be confused with the coagulation protein S made by the PROS gene which this wiki page concerns.
^Kaushansky K, Lichtman M, Prchal J, Levi M, Press O, Burns L, Caligiuri M (2015). Williams Hematology. McGraw-Hill. p. 1926.
^Stenflo J (1999). "Contributions of Gla and EGF-like domains to the function of vitamin K-dependent coagulation factors". Critical Reviews in Eukaryotic Gene Expression. 9 (1): 59–88. doi:10.1615/CritRevEukaryotGeneExpr.v9.i1.50. PMID10200912.
^Rosner W (Dec 1991). "Plasma steroid-binding proteins". Endocrinology and Metabolism Clinics of North America. 20 (4): 697–720. doi:10.1016/S0889-8529(18)30240-8. PMID1778174.
^Beauchamp NJ, Dykes AC, Parikh N, Campbell Tait R, Daly ME (June 2004). "The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population". Br. J. Haematol. 125 (5): 647–54. doi:10.1111/j.1365-2141.2004.04961.x. PMID15147381. S2CID705661.
^García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N (September 2007). "Molecular basis of protein S deficiency". Thromb. Haemost. 98 (3): 543–56. doi:10.1160/th07-03-0199. PMID17849042. S2CID17274778.
Dahlbäck B (1991). "Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system". Thromb. Haemost. 66 (1): 49–61. doi:10.1055/s-0038-1646373. PMID1833851. S2CID24929072.
Witt I (2002). "Molekularbiologische Grundlagen und Diagnostik der hereditären Defekte von Antithrombin III, Protein C und Protein S" [Molecular biological basis and diagnosis of hereditary defect of antithrombin III, protein c and protein S]. Hamostaseologie (in German). 22 (2): 57–66. doi:10.1055/s-0037-1619540. PMID12193972. S2CID58077740.
García de Frutos P, Fuentes-Prior P, Hurtado B, Sala N (2007). "Molecular basis of protein S deficiency". Thromb. Haemost. 98 (3): 543–56. doi:10.1160/th07-03-0199. PMID17849042. S2CID17274778.
Maillard C, Berruyer M, Serre CM, et al. (1992). "Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts". Endocrinology. 130 (3): 1599–604. doi:10.1210/endo.130.3.1531628. PMID1531628.
Griffin JH, Gruber A, Fernández JA (1992). "Reevaluation of total, free, and bound protein S and C4b-binding protein levels in plasma anticoagulated with citrate or hirudin". Blood. 79 (12): 3203–11. doi:10.1182/blood.V79.12.3203.bloodjournal79123203 (inactive 2024-04-10). PMID1534488.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link)
Guglielmone HA, Vides MA (1992). "A novel functional assay of protein C in human plasma and its comparison with amidolytic and anticoagulant assays". Thromb. Haemost. 67 (1): 46–9. doi:10.1055/s-0038-1648377. PMID1615482. S2CID27769717.
Schmidel DK, Tatro AV, Phelps LG, et al. (1991). "Organization of the human protein S genes". Biochemistry. 29 (34): 7845–52. doi:10.1021/bi00486a010. PMID2148110.
Ploos van Amstel HK, Reitsma PH, van der Logt CP, Bertina RM (1991). "Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution". Biochemistry. 29 (34): 7853–61. doi:10.1021/bi00486a011. PMID2148111.
Allaart CF, Aronson DC, Ruys T, et al. (1991). "Hereditary protein S deficiency in young adults with arterial occlusive disease". Thromb. Haemost. 64 (2): 206–10. PMID2148653.
Engesser L, Broekmans AW, Briët E, et al. (1987). "Hereditary protein S deficiency: clinical manifestations". Ann. Intern. Med. 106 (5): 677–82. doi:10.7326/0003-4819-106-5-677. PMID2952034.
Watkins PC, Eddy R, Fukushima Y, et al. (1988). "The gene for protein S maps near the centromere of human chromosome 3". Blood. 71 (1): 238–41. doi:10.1182/blood.V71.1.238.238. PMID2961379.